Increased pressor responses to physostigmine in spontaneously hypertensive rats

Summary Intravenous injection of physostigmine evoked a pressor response in unanaesthetized rats. Spontaneously hypertensive rats (SHR) showed increased pressor responses, but the responses were within normal limits in renal hypertensive and DOCA-saline hypertensive rats. The pressor effect in SHR was abolished by the i.v. injection of atropine sulphate but not by the i.v. injection of atropine methyl bromide. After inhibition of the peripheral muscarinic receptors by atropine methyl bromide, oxotremorine also produced a pressor response in unanaesthetized rats. In contrast to the pressor effect of physostigmine, there was no difference between the oxotremorine-induced pressor response of SHR and that of normotensive Wistar-Kyoto rats. The pressor effect of oxotremorine in SHR was blocked by the i.v. injection of atropine sulphate.     

Central pressor activity of cimetidine in spontaneously hypertensive rats

The systemic blood pressure effect of cimetidine given intracerebroventricularly (i.c.v.) in anaesthetized spontaneously hypertensive (SH) rats has been investigated. Cimetidine (250 μg i.c.v.) caused a gradual long lasting rise in mean in mean arterial blood pressure with maximum of 31·6 ± 4·5 mm Hg. Chemical degeneration of catecholaminergic neurons with 6−OHDA treatment, central administration of phentolamine and prazosin, and the bilaterial adrenalectomy significantly inhibited the pressor response of cimetidine, while propranolol (i.c.v.) had no effect. From these results it appears that the hypertensive response of cimetidine is mediated by central catecholaminergic pathways and is due to an increase in efferent sympathetic outflow and release of catecholamine from the adrenal medulla.     

Pharmacological analysis of the enhanced pressor response to central cholinergic stimulation in spontaneously hypertensive rats

Central cholinergic pressor neurons exist at several levels of the neuraxis. Activation of these neurons in spontaneously hypertensive rats (SHR) can lead to an exaggerated hypertensive response when compared with normotensive control animals (WKY). Our earlier studies demonstrated that intravenous injection of the indirect acting agonist physostigmine, but not the direct agonist arecoline, resulted in an exaggerated pressor response in SHR. The purpose of this study was to determine whether discrete injection of cholinergic agonists directly into the CNS would also result in an exaggerated pressor response in SHR. Cholinergic pressor neurons in the posterior hypothalamus may be activated following injection of cholinergic agonists into the lateral cerebral ventricles (l.c.v. injection). Cholinergic pressor neurons in the medulla may be activated following injection of agonists into the cisterna magna (i.c. injection). L.c.v. injection of arecoline in freely-moving animals evoked a pressor response in both SHR and WKY rats that was not significantly different between the two strains. Prior depletion of brain acetylcholine with hemicholinium-3 did not affect the pressor response to l.c.v. arecoline, confirming the postsynaptic site of action of the agonist. Surprisingly, l.c.v. injection of physostigmine also did not result in an exaggerated pressor response in SHR. In contrast, injection of physostigmine into the cisterna magna did produce an enhanced hypertensive response in SHR compared to WKY rats. These results are consistent with the presence of two cholinergic pressor systems; however, only the medullary cholinergic system appears to play a prominent role in spontaneous hypertension. Also the hypothalamic (rostral) cholinergic system does not appear to directly interact with the caudal system.     

Age-related changes of in vivo beta-adrenergic responsiveness in normotensive and spontaneously hypertensive rats

The variations of plasma cyclic AMP concentration caused by propranolol and isoproterenol were studied in order to investigate endogenous stimulation and responsiveness of the beta-adrenoceptor-cyclic AMP system in vivo, in 7 and 18 week old unanaesthetized male SHR and WKY. In both age groups, the basal cyclic AMP level was higher in SHR than in controls but was significantly reduced to a comparable value in the two strains after intraperitoneal injection of 2.5 mg X kg-1 propranolol, a dose which markedly depressed or even abolished the effect of isoproterenol. Cumulative dose-response curves of plasma cyclic AMP concentration obtained in another group of rats after successive subcutaneous injections of isoproterenol showed that the ED50 value of this drug was higher in SHR than in WKY and increased in a parallel manner in the two strains between 7 and 18 weeks of age (respectively from 0.21 +/- 0.01 to 0.34 +/- 0.02 mumol X kg-1 in WKY and from 0.32 +/- 0.02 to 0.52 +/- 0.03 mumol X kg-1 in SHR). At the same time blood pressure increased much less markedly in WKY (from 115 +/- 4 to 119 +/- 2 mm Hg) than in SHR (from 134 +/- 3 to 179 +/- 3 mm Hg). Altogether these results show that endogenous beta-adrenergic stimulation of the cyclic AMP system was higher in SHR of both ages in spite of a diminished responsiveness of this system to exogenous isoproterenol.     

Cardiovascular responses to morphiceptin in spontaneously hypertensive and normotensive rats

In the urethane anesthetized spontaneously hypertensive rats (SHR) intraventricular injections of morphiceptin produced dose-related increase in heart rate and blood pressure. In contrary, intraventricular administration of morphiceptin in Wistar rats induced a fall in blood pressure and heart rate. Yohimbine antagonized pressor responses to morphiceptin in SHR. Naloxone counteracted both the stimulatory effects of morphiceptin in SHR as well as hypotensive responses in Wistar rats. Bilateral vagotomy blocked depressant action of morphiceptin in normotensive but failed to alter the pressor effects in SHR rats. After systemic injections of morphiceptin a fall in heart rate and blood pressure was obtained in both strains.     

Exaggerated pressor response to centrally administered renin in freely moving, spontaneously hypertensive rats

The cardiovascular responses to intracerebroventricular (i.c.v.) injection of renin were compared between freely moving normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The i.c.v. injection of renin (0.05-1.0 mU) produced a dose-dependent and a long-lasting rise in mean blood pressure associated with variable changes in heart rate (HR) in both WKY and SHR. However, the blood pressure and HR were not affected by intravenously injected renin (0.1 mU). The pressor response to i.c.v. injected renin was greater in SHR than in WKY, the dose-response curve for renin in SHR being to the left of that in WKY. Central (i.c.v.) pretreatment with [Sar1, Ile8]angiotensin II (50 micrograms) largely abolished the pressor response to i.c.v. injected renin in both WKY and SHR. The i.c.v. injection of angiotensin II (ANG II) (10-100 ng) induced a dose-dependent pressor response which was antagonized by central pretreatment with [Sar1, Ile8]ANG II (50 micrograms). The pressor response to ANG II was also greater in SHR than in WKY. These results suggest that the pressor response to centrally administered renin as well as to ANG II, which is mediated via ANG II receptors located in the brain, is enhanced in SHR.     

Cardiovascular responses in spontaneously hypertensive rats with acute renal failure

Cardiovascular status and reactivity have been investigated in spontaneously hypertensive rats (SHR) with glycerol-induced acute renal failure. SHR with acute renal failure had significantly lower mean arterial blood pressures and heart rates. The pressor responses to noradrenaline and the chronotropic responses to right cervical sympathetic and vagal nerve stimulation were diminished in uraemic SHR compared to control SHR. The cardiovascular depression observed in SHR with acute renal failure was similar to that previously noted in normotensive rats with acute renal impairment.     

Restraint alters temperature responses to cocaine in spontaneously hypertensive rats

The body temperature responses to intraperitoneal (IP) or intravenous (IV) cocaine in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were examined under restrained and freely moving conditions. Resting values for rectal temperature (RT), in ambient temperatures of 22-24 degrees C, were significantly (p less than 0.01) higher in SHR than in WKY rats, under both restrained (39.19 +/- 0.07 vs. 38.01 +/- 0.06 degrees C) and freely moving (39.39 +/- 0.08 vs. 38.08 +/- 0.06 degrees C) conditions. Resting RT did not differ between restrained and freely moving conditions within a strain. An heterogeneity of RT response to both IV and IP cocaine was expressed by restraint in SHR. The SHR could be divided into animals which demonstrated hyperthermia to cocaine (SHRH) and those in which RT fell (SHRL) . However, cocaine produced hyperthermia in all freely moving SHR, regardless of the route of administration. The effects of IV cocaine in restrained WKY rats were similar to those in freely moving SHR, whereas IP cocaine decreased RT in all restrained WKY rats. Under conditions of restraint, divergent RT responses to cocaine were demonstrated following IV and IP administration in WKY rats, but not in SHR. These results indicate that restraint stress can significantly modify the body temperature responses to acute cocaine administration in both SHR and WKY rats.     

Selective suppression of pressor and sympathetic responses to centrally infused TRH in hypothyroid rats

To determine whether hypothyroidism alters responsiveness to centrally infused thyrotropin-releasing hormone (TRH), blood pressure and sympathetic nerve responses to various stimuli were recorded in urethane-anesthetized rats. Four weeks after thyroidectomy or treatment with propylthiouracil, pressor responses elicited by intracerebroventricular- (ICV)-infused TRH or by electrical stimulation of the posterior or ventromedial hypothalamus were always accompanied by increased sympathetic nerve activity in all rats. When serum thyroxine levels were lowered in hypothyroid rats, pressor responses to most stimuli, including intravenous injections of norepinephrine, angiotensin, and vasopressin, were inhibited, indicating that peripheral pressor responsiveness had been reduced. For centrally acting stimuli, pressor inhibition was also considered partly caused by a selective decrease in sympathetic vasomotor tone because sympathetic excitation was reduced only during ICV infusions of TRH, but not during posterior hypothalamic stimulation. On the other hand, there was no obvious explanation why both pressor and sympathetic responses to ventromedial hypothalamic stimulation were spared from inhibition. Because sympathetic nerve responses to ICV-infused TRH were reduced by thyroid suppression, these results imply that sympathetic activation by TRH in intact rats is mediated, at least in part, indirectly by way of TRH stimulation of thyroid activity.     

Effect of inhibition of central angiotensin pressor mechanisms on blood pressure in spontaneously hypertensive rats

The present experiments were designed to elucidate the role of central angiotensin II (AII) mechanisms in maintenance of established hypertension in adult spontaneously hypertensive rats (SHR) by determining the blood pressure response to chronic intraventricular (i.v.t.) infusion of the converting enzyme inhibitor teprotide or the AII receptor antagonist 1sar,8Thr-AII (sarthran). Male SHR (240-300 g) were given chronic indwelling arterial and venous catheters and bilateral lateral cerebral ventricular cannulae. The acute pressor responses to successive intravenous infusions of AII (sarthran experiments) or angiotensin I (AI; teprotide experiments) and to an intraventricular bolus injection of AII or AI were determined in the conscious rats. A 5-day intraventricular infusion of sarthran (1 or 6 micrograms/h) or teprotide (10 micrograms/h) in isotonic saline was maintained by subcutaneously implanted osmotic minipumps, and pressor responses were retested on the 5th day of intraventricular infusion. Five-day intraventricular sarthran infusion at 1 and 6 micrograms/h reduced the pressor response to intraventricular AII by 48 and 74%, respectively, while intraventricular teprotide (10 micrograms/h) inhibited the pressor response to intraventricular AI by 25%. None of the intraventricular infusions significantly decreased pressor responsiveness to intravenous AII or AI. In separate groups of SHR, tail-cuff blood pressure was monitored before, during, and after a 1-week intraventricular teprotide infusion (10 micrograms/h) or successive intraventricular infusions of sarthran at 1 microgram/h for 2 weeks followed by 6 micrograms/h for 1 week. Neither chronic intraventricular sarthran or teprotide caused a significant lowering of blood pressure in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Central alpha 2-adrenoceptor-mediated pressor response to clonidine in conscious, spontaneously hypertensive rats.

Pressor responses to intracerebroventricular (i.c.v.) injection of clonidine were investigated in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Clonidine (1-10 micrograms, i.c.v.) caused a dose-dependent pressor response and decrease in heart rate in both SHR and WKY. In SHR, low doses (1, 2.5 micrograms) but not high doses (5, 10 micrograms) of i.c.v.-clonidine induced a depressor response following the pressor response. Both pressor and depressor responses to i.c.v.-clonidine were significantly greater in SHR than in WKY. In both SHR and WKY, pressor responses to i.c.v.-clonidine were abolished by pentobarbital anesthesia, pretreatment with i.v.-furosemide (5 mg/kg), 24-hr water deprivation and pretreatment with i.c.v.-yohimbine (100 micrograms), but not by pretreatment with i.v.-yohimbine (100 micrograms) and i.c.v.-prazosin (10 micrograms). On the 1st day after surgery for arterial catheter implantation, SHR reduced their water intake, and i.c.v.-clonidine (5 micrograms) caused a slight pressor response, whereas the same dose of clonidine on the 7th day after surgery resulted in a marked pressor response. These results suggest that clonidine caused a central alpha 2-adrenoceptor-mediated pressor response, which is greater in SHR than in WKY and is sensitive to body fluid volume changes and anesthesia.     

Haemodynamic responses to NG-monomethyl-L-arginine in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

1. Nitric oxide (NO) is a major component of endothelium-derived relaxing factor (EDRF) the synthesis of which from L-arginine can be inhibited by NG-monomethyl-L-arginine (L-NMMA). To assess whether basal NO tone is different in experimental hypertension, the haemodynamic effects of L-NMMA have been compared in anaesthetized spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats in which autonomic reflexes were blocked by ganglion blockade. 2. Bolus intravenous injections of L-NMMA, 1-30 mg kg-1, but not D-NMMA, 1-30 mg kg-1, induced dose-related increases in mean arterial pressure and decreases in conductances in the renal, carotid, hindquarters and mesenteric vascular beds in both SH and WKY rats. Although the different vascular beds varied in their maximum responses to L-NMMA, there were neither qualitative nor quantitative differences between the two rat strains in this respect. 3. The effects of L-NMMA, 30 mg kg-1, i.v. on all parameters were rapidly and completely reversed by L-arginine, 30 mg kg-1, i.v., in both SH and WKY rats. 4. The results indicate that NO derived from L-arginine exerts a powerful vasodilator tone in both anaesthetized, ganglion-blocked SH and WKY rats. Although NO appears to contribute differentially to tone in the different vascular beds, there were no major differences between the two rat strains in this respect. Hence a reduced NO tone to the vasculature is unlikely to be a major factor contributing to the elevated blood pressure in the adult SH rat.     

Quinapril treatment and arterial smooth muscle responses in spontaneously hypertensive rats.

1 The effects of long-term angiotensin-converting enzyme inhibition with quinapril on arterial function were studied in spontaneously hypertensive rats, Wistar-Kyoto rats serving as normotensive controls. 2 Adult hypertensive animals were treated with quinapril (10 mg kg-1 day-1) for 15 weeks, which reduced their blood pressure and the concentrations of atrial natriuretic peptide in plasma and ventricular tissue to a level comparable with that in normotensive rats. 3 Responses of mesenteric arterial rings in vitro were examined at the end of the study. Compared with normotensive and untreated hypertensive rats, responses to noradrenaline were attenuated in hypertensive animals on quinapril, both force of contraction and sensitivity being reduced. Quinapril also attenuated maximal contractions but not sensitivity to potassium chloride. Nifedipine less effectively inhibited vascular contractions in normotensive and quinapril-treated than in untreated hypertensive rats. 4 Arterial relaxation responses by endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitrite, isoprenaline) mechanisms were similar in normotensive and quinapril-treated rats and more pronounced than in untreated hypertensive rats. 5 Cell membrane permeability to ions was evaluated by means of potassium-free solution-induced contractions of endothelium-denuded denervated arterial rings. These responses were comparable in normotensive and quinapril-treated rats and less marked than in untreated hypertensive rats. 6 Intracellular free calcium concentrations in platelets and lymphocytes, measured by the fluorescent indicator quin-2, were similar in normotensive and quinapril-treated rats and lower than in untreated hypertensive rats. 7 In conclusion, quinapril treatment improved relaxation responses and attenuated contractions in arterial smooth muscle of hypertensive rats. These changes may be explained by diminished cytosolic free calcium concentration, reduced cell membrane permeability, and alterations in dihydropyridine-sensitive calcium channels following long-term angiotensin-converting enzyme inhibition.     

Enhanced vasodilatory responses to bradykinin in stroke-prone spontaneously hypertensive rats.

Vasodilatory responses to bradykinin (BK) and acetylcholine (ACh) were compared in phenylephrine preconstricted perfused kidneys from 30-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Responses to ACh did not differ between kidneys from SHRSP and WHY. BK-induced dilatation was greater in kidneys from SHRSP relative to WHY and was not affected by indomethacin or captopril. These results indicate that renal vasodilatory responsiveness to bradykinin is enhanced in SHRSP with established hypertension.     

Norepinephrine-synthesizing enzymes in brain, adrenals and peripheral sympathetic nerves of spontaneously hypertensive rats.

Dopamine-beta-hydroxylase (DBH) activity in serum, DBH and tyrosine hydroxylase (TH) activities in mesenteric vessels, and DBH and TH activities in locus coeruleus and hypothalamus of brain did not differ significantly between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKR) at 16 weeks of age when hypertension of SHR was fixed. In contrast, DBH and TH activities in vas deferens and adrenal glands were significantly higher in SHR than in WKR. These changes in SHR at 16 weeks of age after establishment of hypertension are directly opposite those reported previously in SHR at 3 weeks of age before the onset of hypertension.     

New approach for measurement of sympathetic nervous abnormality in conscious, spontaneously hypertensive rats

We previously reported a highly sensitive chemiluminescence high-performance liquid chromatographic method to determine catecholamines in plasma. In this study, we employed this method to measure the cardiac function and plasma norepinephrine (NE) concentration in conscious rats. Benidipine, 1,4-dihydropyridine calcium antagonist (4 mg/kg), and beta-blocker (propranolol, 30 mg/kg) were administered orally to conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats, and blood pressure, heart rate and plasma NE levels were measured. Plasma NE concentration was used as an index of sympathetic nervous system activity in conscious rats. The basal plasma NE levels were significantly higher in SHRs than in WKY rats (P<0.05), indicating the activity of the basal sympathetic nervous system in SHRs was elevated. The sensitivity of the baroreflex-mediated sympathetic nervous response was reduced in SHRs as compared to that in WKY rats. The concomitant administration of benidipine and a beta-blocker decreased heart rate without affecting the baroreflex-mediated sympathetic nervous response, indicating that propranolol might suppress mainly the cardiac beta-adrenoceptor. The present study suggested the high activity of the basal sympathetic nervous system and the reduced response of the baroreflex-mediated sympathetic nervous system in SHRs compared to WKY rats in the conscious condition.     

Possible involvement of an impaired baroreflex mechanism but not the renin-angiotensin system and vasopressin in the enhanced pressor responsiveness to physostigmine in spontaneously hypertensive rats

Effects of physostigmine on heart rate, mean arterial pressure (MAP), plasma renin concentration (PRC) and vasopressin (AVP) release were investigated in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Physostigmine (100 micrograms/kg, i.a.) produced a greater and prolonged hypertensive response in the SHR than in the WKY. Heart rate was increased by physostigmine in SHR rats while it was unchanged in the WKY. PRC was unchanged or even slightly decreased in these animals when MAP was increased by physostigmine. An AVP pressor antagonist did not attenuate the pressor and cardiac effects of physostigmine in these animals. These data indicate that an impaired baroreflex mechanism or a different mode of sympathetic neuronal activation by physostigmine through the central mechanism appears to be contributory, at least in part, to the enhanced pressor responsiveness in the SHR. The renin-angiotensin system and AVP do not appear to be involved in the enhanced pressor responsiveness to physostigmine in SHR rats.